1,5-Dimethyl N-[(1,1-dimethylethoxy)carbonyl]-L-glutamate

Proceeding from L-glutamic acid methyl ester hydrochloride (7a), the vinylproline derivative 14a was prepared in seven steps (scheme 4). The key steps were firstly the diastereo selective allylation of 8a to 9a, and the isomerization of the double bond (12a to 12b)7.4 g L-glutamic acid(6, 50.0 mmol) and 100 ml of methanol were added to the reaction flask. To the flask was added dropwise 32 ml of trimethylchlorosilane (TMSC1, 250.0 mmol) at room temperature and the mixture was stirred at room temperature for 6 hours. The esterification reaction was terminated by TLC. To the reaction system was added 49 ml of triethylamine (Et3N, 350.0 mmol) and 13.2 g of Boc20 (60. 0 mmol) at 0 ° C, and the mixture was stirred at room temperature for 48 hours. Ethyl acetate (200 ml) and water (100 ml) were added to the residue, and the mixture was partitioned by shaking. The aqueous phase was extracted with ethyl acetate (100 mL χ 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, Column chromatography to obtain 13.1 g of glutamic acid ester (7). The overall yield in 2 steps was 95percent.Acetyl chloride (5 mL) was slowly added dropwise to methanol (100 mL) at 0° C., stirred for 5 minutes, then glutamic acid (10 g, 67.9 mmol) was added, stirring was continued and the mixture was heated to reflux for 2 hours while maintaining the reflux temperature. .The reaction was stopped and the solvent was removed under reduced pressure and recrystallized from ether. The resulting oil was dissolved in THF (150 mL) and TEA (28.5 mL, 203.7 mmol) was added dropwise at 0°C.After stirring at 0° C. for 5 minutes, di-tert-butyl dicarbonate (17.8 g, 81.5 mmol) dissolved in THF (30 mL) was continuously added dropwise, and the mixture was stirred at room temperature for 2.5 hours.After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was added with water (200 mL), extracted with DCM (2×200 mL) from the aqueous phase, and the combined organic phases were dried over anhydrous sodium sulfate.After concentration, the resulting crude product was purified by flash column (PE:EA=5:1) to give N-Boc-L-(+)-glutamic acid dimethyl ester (17.7 g, yield 95.2percent) as none Oily liquidH-CI(S)-(Tetrahydro-pyran-3-yl)amine hydrochloride (S)-Dimethyl 2-(tert-butoxycarbonylamino)pentanedioateTo MeOH (7L) was added TMSC1 slowly at 0 °C, and the mixture was stirred for 30 min, then L-glutamic acid (700 g, 4.76 mol) was added to the mixture. The mixture was stirred at room temperature until complete reaction was observed (monitored by TLC). After cooling to 0 °C, triethylamine (313 g, 31.0 mol) and BocFreshly distilled thionyl chloride (0.60 mL, 8.16 mmol) was added dropwise with stirring to a cooled suspension of l-glutamic acid (1.0 g, 6.8 mmol) in anhydrous methanol (7 mL). The reaction mixture was stirred at rt for 2 h and was refluxed for 8 h. The solvent was removed under reduced pressure and co-evaporated with methanol (3.x.7 mL) to afford crude product as sticky liquid. To a solution of this crude product in THF (20 mL) were added triethylamine (2.0 mL, 14.6 mmol) and a solution of di-tert-butyl dicarbonate (1.78 g, 8.16 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at rt for 8 h. After completion of the reaction, solvent was removed in vacuo and the residue partitioned between AcOEt (20 mL) and water (20 mL). The aqueous phase was extracted with AcOEt (2.x.15 mL) and the combined organic layers were washed with 3percent HCl (15 mL), saturated NaHCO[0027] To a stirred solution of (S)-Glutamic acid (100 g, 0.68 mol) in dry methanol (1740 ml) was added TMSC1(375 ml, 2.9 mol) at 0° C. After addition, the mixture was allowed to reach room temperature and stirred overnight. NEtTrimethylsilyl chloride (107.8 g, 1.00 mol) was added dropwise to a cooled solution of L-glutamic acid (30.00 g, 0.20 mol) in 300 mL of methanol at 0 [XB0;C.] The resulting clear, colorless solution was allowed to stir at room temperature. After 18 h, analysis by thin layer chromatography (30percent ethyl acetate in hexane) showed that no starting material remained. The reaction was then cooled to 0 [XB0;C, ] triethylamine (134 g, 1.33 mol) was added, and a white precipitate formed. Di-tert- [BUTYIDICARBONATE] (49 g, 0.23 mol) was added, and the mixture was allowed to warm to room temperature. After 3 h the solvent was removed, and 700 mL of diethyl ether was added. The solution was filtered, and the filter cake was rinsed with an additional 500 mL of diethyl ether. The filtrate was concentrated to 60.8 g [(GT;95percent)] of a tan oil which was carried onto the next step without further purification. LCMS: [M/Z = 298.] 1 [M+Na] +. HRMS calcd. [FOR C12H21NO6] : 276.1447 [M+H] +, found: 276.1462. [1H NMR (CDCI3) 6] 1.45 (s, 9H), 1.95 (m, 1 H), 2.50 (m, 1 H), 2.40 (m, 2H), 3.69 (s, 3H), 3.75 (s, 3H), 4.32 (m, 1H), 5.15 (m, [1H).]L-glutamic acid (6. 0g, 40.78 [MMOL)] was dissolved in methanol (100 mL). To the reaction mixture trimethylsilyl chloride (22.9 mL, 180 [MMOL)] was added at 0 [XB0;C] under nitrogen and allowed to stir overnight. To the reaction mixture at 0 ° C under nitrogen triethylamine (37 mL, 256 [MMOL)] and [DI-TERT-BUTYIDICARBONATE] (9.8 g, 44.9 [MMOL)] was added and stirred two hours. The solvent was removed and the residue was triturated with ether (200 mL). The triturated mixture was filtered. The filtrate was evaporated to an oil and chromatographed on silica, eluting with ethyl acetate and hexane, to give the mono boc L-glutamic diester (10.99 g, 98percent).To a solution of TMSCI (200 mL, 1 .60 mol) in MeOH (500 mL) was added L- giutarnic acid (47 g, 319 mrnoi) as portions at 0 °C After addition, the reaction mixture was stirred at 10 °C for 15 lirs. The reaction mixture was concentrated to afford dirnethyl (2S)2- aminopentanedioate (67 g, yield 99.1percent) as colorless oil, which was used to next directly without further purification.To a solution of dimethyl (25>2.-aminopentanedioate (67 g, 3 16.58 mmol) in MeOH (500 mL) was added TEA (132 mL, 949.74 mmol) and (Boc)20 (90 g, 411.55 mmol) at 0°C slowly. After addition, the reaction mixture was stirred at 10 0Q for 14 hrs. The mixture was concentrated and the residue was dissolved in EtOAc (500 mL), the mixture was washed with 0.5 N HCI (300 mL), sat. NaT:1C03 (300 mL), and biine (300 mL). The organic layers was dried over Na2SO4 and concentrated in vacuo to afford compound 26A (75 g, yield 86.05percent) as colorless oil. R NMR (400 MHz, CDCI3): 5.17 5.05 (m, IH), 4.40 4.28 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.49 2.33 (m, 2H, 2.25 2.13 (m, 1H), 2.02 1.89 (m, 1H), 1.44 (s, 9E1). MS (ESI) in/z (M-F-23) 2979.Proceeding from L-glutamic acid methyl ester hydrochloride (7a), the vinylproline derivative 14a was prepared in seven steps (scheme 4). The key steps were firstly the diastereo selective allylation of 8a to 9a, and the isomerization of the double bond (12a to 12b)A solution of 2 (S) -amino-pentanedioic acid dimethyl ester hydrochloride (24.3 g, 115 mmol) in methanol (150 [ML)] is treated with triethylamine (31.5 [ML, ] 226 mmol). Solid di-tert-butyl dicarbonate (33 g, 151 mmol) is added. After 18 hours the solvent is removed and the residue is dissolved in [CH2CL2.] The solution is washed twice with IN [HC1, ] once with brine and dried over [NA2S04.] The spent dessicant is removed and the solvent is evaporated to give the desired product.2 [(S)-TERT-BUTOXYCARBONYLAMINO-PENTANEDIOIC] acid dimethyl ester A solution of 2 [(S)-AMINO-PENTANEDIOIC] acid dimethyl ester hydrochloride (8.12 g, 38.4 mmol) in methanol (50 mL) is treated with triethylamine (10.5 [ML, ] 75.3 mmol) and solid di-tert-butyl dicarbonate (10.91 g, 50.0 mmol). After 18 hours the solvent is removed, the residue is dissolved in [CH2CL2, ] and the solution is washed with IN [HC1] (2 x 10 mL) and brine (1 x 5 mL). After drying the solution over [NA2S04] and removing the spent dessicant by filtration, the solvent is evaporated to leave the desired product.Example 1Synthesis of (S)-SOCl2 (50 mL, 689 mmol) was added dropwise to a mixture of L-glutamic acid (25 g, 170 mmol) in MeOH (500 mL) at 0 C. Then the reaction mixture was refluxed for 5 h and evaporated under reduced pressure to give a white salt. The resulting ammonium salt was used directly in the next step.A solution of ammonium salt, di-tert-butyl dicarbonate (39mL, 170 mmol), Et3N (24 mL, 170 mmol) and DMAP (2.1 g, 17 mmol) in 1, 4-dioxane/H2O (300:300 mL) was stirred over night. The reaction mixture was partitioned between 0.5 N aqueous HCl (200mL) and CH2Cl2 (300 mL). The aqueous phase was further extracted with CH2Cl2 (300 mL × 2). The combined organic layers were dried over Na2SO4 and evaporated. The residue was used directly in the next step.A solution of residue, di-tert-butyl dicarbonate (47 mL, 200 mmol) and DMAP (4.2 g, 34 mmol) in CH3CN (400 mL) was stirred over night. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EA (400 mL) and washed with 0.2 N aqueous HCl (200 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA 5:1) to give a white solid (38.9 g, 61% yield). 1H NMR (400 MHz, CDCl3) 4.95-4.91 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.49-2.16 (m, 4H), 1.49 (s, 18H). 13C NMR (100 MHz, CDCl3) 173.1, 170.8, 151.9, 83.3, 57.3, 52.2, 51.6, 30.6, 27.9, 25.2. MS (ESI, m/z) found 398.1 ([M+Na]+). [alpha]25D = - 38.2 (c 0.061, EtOAc).(c) Preparation of addition norvaline in L-form This compound was prepared with reference to the method described in Tetrahedron: Asymmetry 9 (1998) 3381-3394. L-glutamic acid (10 g) (1 eq) was dissolved in 90 ml of dry MeOH and 40.4 g (5 eq) of thionyl chloride was added dropwise over 30 minutes under an ice bath, followed by stirring overnight and further concentration. The residue was dissolved again in 150 ml of dry MeOH, and 44.7 g (6.5 eq) of Et3N and 16.3 g 1.1eq) of (Boc)2O were added under an ice bath, followed by stirring for 6 hours. The reaction solution was concentrated and extracted by liquid separation using ethyl acetate, and then the organic layer was washed with 10% citric acid and washed with saturated NaHCO3 and Brine. After drying over sodium sulfate, concentration and purification by silica gel column chromatography were performed, and 17.8 g (95%) of pale yellowish brown oily dimethyl (S)-2-tert-butoxycarbonylamino-pentanodioate was obtained.A solution of lithium hexamethyldisilylazide (152.6 [ML, ] 1M in THF, 152.6 mmol) is cooled under argon in a dry ice/acetone bath. A solution [OF 2 (S)-TERT-BUTOXYCARBONYLAMINO-PENTANEDIOIC] acid dimethyl ester (20 g, 72.6 mol) in THF (200 mL) is added via cannula, maintaining the temperature [BELOW-60 C.] After 30 minutes at-78C methyl iodide (9 mL, 145 mmol) is added as rapidly as possible via cannula. The reaction mixture is [STIRRED-78C] for 4.5 hour and then quenched with 1 [N] [HC1] (190 mL). The aqueous layer is extracted with EtOAc (3 x 350 mL). The combined extracts are washed with saturated [NAHCO3] and brine, dried over [NA2S04, ] and concentrated to give a yellow oil which is purified by flash chromatography using 20 % EtOAc/hexanes.Synthesis of (2S, 45)-2-tent-butoxycarbonylamino-4-methyl-pentanedioic acid dimethyl ester (compound 3b) 1 M LiHMDS in THF (1500 mL) was charged into a five-liter four-necked flask at -78 C. under nitrogen. To this was added dropwise a solution containing crude compound 2b (210 g in 1000 mL dry THF) at

Molecular Weight:275.30
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:9
Exact Mass:275.13688739
Monoisotopic Mass:275.13688739
Topological Polar Surface Area:90.9
Heavy Atom Count:19
Complexity:334
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes